Neoadjuvant Atezo, Adjuvant Atezo + Beva Combined With RF Ablation of Small HCC: a Multicenter Randomized Phase II Trial (AB-LATE02)

  • STATUS
    Recruiting
  • End date
    Jul 24, 2027
  • participants needed
    202
  • sponsor
    University Hospital, Montpellier
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Updated on 4 October 2022
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Summary

Following the results of study IMbrave150, the combination Atezolizumab + Bevacizumab is a promising treatment option for patients with HCC.

In addition, the high intrahepatic distant recurrence rate and accumulating evidence for a metastatic mechanism encourages exploring adjuvant/neoadjuvant strategies targeting tumor growth and metastatic escape in the context of percutaneous thermal ablation for small HCC.

Local ablation of HCC is therefore an "ideal" setting for testing atezolizumab + bevacizumab in combination with ablation, with the aim of reducing the risk of recurrence.

Description

Liver cancer is the sixth most common cancer and the third leading cause of death from cancer worldwide (source: Globocan 2018). Hepatocellular carcinoma (HCC) represents 80-90% of liver cancers. Percutaneous thermal ablation (PTA) is a validated treatment option for very early and early stage HCC, together with surgical resection and liver transplantation (EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma, J Hepatol 2018). Due to its excellent tolerance, particularly in patients with portal hypertension or bearing comorbidities, it now represents in France nearly 70% of the first-line curative treatment of "in Milan" tumours. The risk of local tumor progression (LTP) is ≈10-20% in PTA series (Nault, J Hepatol 2018; N'Kontchou et al., Hepatology (Baltimore, Md) 2009). In addition, the long-term results of PTA are influenced by the high rate (up to 60-80% at 5 years) of intrahepatic distant recurrence (IDR) (Nault et al., J Hepatol 2018), as observed also after HCC surgical resection (EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma, J Hepatol 2018; Imamura et al., J Hepatol 2003). It is unknown whether early IDR (2-3 years after PTA of <3 cm HCC) is due to metastatic spread or de novo carcinogenesis.

Strong scientific rationale and emerging clinical data suggest that the combined vascular endothelial growth factor (VEGF) / Programmed death-ligand 1 (PD-L1) blockade may be clinically beneficial in a number of tumor types, including HCC. Therefore, local ablation in HCC is an " ideal " context to test Atezolizumab + Bevacizumab in combination with ablation. The investigators hypothesized that the combo of Atezolizumab + Bevacizumab and radiofrequency ablation could improve recurrence-free survival (RFS) at 2 years.

The aim of this randomized multicentre phase II trial is to compare RFS at 2 years in the experimental arm (Atezolizumab + Bevacizumab + RF ablation) versus the control arm (RF ablation) according to HCC modified response evaluation criteria in solid tumours (mRECIST). Thus the proposed use here of Atezolizumab as first neoadjuvant, then in combination with Bevacizumab as adjuvants, should theoretically, and hopefully, limit the radiofrequency ablation (RFA) pro-tumor effects. The RFS current rate value of 45% corresponding to the standard procedure of RFA alone (i.e. in the Active Comparator arm) should be increasing to at least 65% because of the addition of the biotherapy (i.e. in the Experimental arm). The patients' recruitment timeframe is set at 36 months and the patient's follow-up timeframe is 5 years. 202 patients are to be included, 101 per arm.

Details
Condition Hepatocellular Carcinoma
Treatment Atezolizumab (neoadjuvant), Percutaneous Radiofrequency, Bevacizumab (adjuvant), Atezolizumab (adjuvant)
Clinical Study IdentifierNCT04727307
SponsorUniversity Hospital, Montpellier
Last Modified on4 October 2022

Eligibility

 Yes No Not Sure

Inclusion Criteria

Male or female patients ≥ 18 years of age
Diagnostic of HCC based on Imaging (EASL guidelines)
Patients with HCC eligible for ablation as assessed by multidisciplinary board
All HCC nodules <3cm
-3 nodules of HCC
At least one uni-dimensional measurable lesion by magnetic resonance imaging (MRI)
Liver function status Child-Pugh Class A
according to modified RECIST criteria
Adequate bone marrow, liver and renal function as assessed by the following laboratory
Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1
tests
Hemoglobin > 8.5 g/dL
Absolute neutrophil count ≥ 1500/mm3
Platelet count ≥ 50,000/ mm3
Total bilirubin ≤ 2 mg/dL (ou ≤ 34 µmol/ L)
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x upper limit of normal (ULN)
Serum creatinine ≤ 1.5 x ULN
Prothrombin time > 50%
Lipase ≤ 2 x ULN
Glomerular Filtration Rate (GFR) ≥ 35 mL/min/1.73 m2
Women of childbearing potential and men must agree to use adequate contraception
Life expectancy ≥ 3 months
Patients affiliated to a Social Security System

Exclusion Criteria

Patients with contraindications to ablation or atezolizumab or bevacizumab
Patients with contraindication to contrast medium intravenous injection either gadolinium or iodinate
Patients with contraindication to MRI
Prior liver transplantation
Child-Pugh B or C
Patients with mixed histology (HCC and cholangiocarcinoma, namely hepatocholangiocarcinoma), if a biopsy is available
Current or recent (≤ 10 days prior to initiation of study treatment) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose. Prophylactic anticoagulation for the patency of venous access devices is allowed provided the activity of the agent results in an INR < 1.5 x ULN and aPTT is within normal limits within 14 days prior to initiation of study treatment. For prophylactic use of anticoagulants or thrombolytic therapies, the approved dose as described by local label may be used
Current or recent (≤10 days prior to initiation of study treatment) use of aspirin (> 325 mg/day) or treatment with clopidogrel, dipyramidole, ticlopidine, or cilostazol
Portal vein invasion, whatever its extent, shown on baseline imaging
Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study
Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions
Patients with extra-hepatic metastases, either previously-treated or not. One lung nodule (<5mm) is allowed. Calcified lung micronodules as well as typical intra-pulmonary lymph nodes are allowed. Hepatic hilum lymph node < 10mm (short axis) is allowed
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study
Prior surgery of HCC with micro- or macro-vascular invasion demonstrated at pathology
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are
met
Prior systemic treatment for HCC, in particular agents targeting T-cell costimulation or checkpoint pathways (including those targeting PD-1, PD-L1 or PD-L2, cluster of differentiation 137 (CD137), or cytotoxic T-lymphocyte antigen (CTLA-4))
Rash must cover < 10% of body surface area
Patients with uncontrolled HBV infection and viral load above 500 IU/mL
Disease is well controlled at baseline and requires only low-potency topical corticosteroids
Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high risk for bleeding. Patients must undergo an esophagogastroduodenoscopy (EGD), and all size of varices (small to large) must be assessed and treated per local standard of care prior to enrollment. Patients who have undergone an EGD within 6 months of prior to initiation of study treatment do not need to repeat the procedure
No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids
Past or concurrent history of neoplasm other than HCC, except for in-situ carcinoma of the cervix uteri and/or non-melanoma skin cancer and superficial bladder tumors. Any cancer curatively treated > 3 years prior to study entry is permitted
Known history or symptomatic meningeal tumors
Treatment with systemic immunosuppressive medication (including, but not limited to
Patients who received acute, low-dose systemic immunosuppressant medication or a onetime pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study after Medical Monitor confirmation has been obtained
Patients with phaeochromocytoma
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide
Ongoing infection : Hepatitis B is allowed if no active replication is present (HBV replication below 500 IU/mL) or Hepatitis C is allowed if no antiviral treatment is required
and anti-TNF-α agents) within 2 weeks prior to initiation of study treatment
Prior chemo-embolization or radio-embolization
or anticipation of need forsystemic immunosuppressive medication during study
Arterial or venous thrombotic or embolic events such as cerebrovascular accident, deep vein thrombosis or pulmonary embolism within 6 months before enrolment
treatment, with the following exceptions
Any psychological, familial, sociological, geographical or illness or medical condition that could jeopardize the safety of the patient and/or his compliance with the study protocol and follow-up procedure
Known history of human immunodeficiency virus (HIV) infection
Seizure disorder requiring medication
Non-healing wound, ulcer or bone fracture
Breast feeding
Pregnancy
Legal incapacity (persons in custody or under guardianship)
Deprived of liberty Subject (by judicial or administrative decision)
Grade 3 (severe) hypertension ≥160 and/or ≥100 mmHG (systolic and diastolic, according to NCI-CTCAE v5.0)
Clinically significant bleeding NCI-CTCAE version 5.0 ≥ Grade 3 within 30 days before enrolment (transfusion indicated)
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